Several types of self-hardening calcium phosphate compositions have been studied (Brown and Chow, A New Calcium Phosphate Water Setting Cement, pp. 352-379 in Brown, Cements Research Progress, American Ceramic Society, OH, 1986; Ginebra et al., Setting Reaction and Hardening of an Apatitic Calcium Phosphate Cement, J. Dent. Res. 76:905-912, 1997; Constantz et al., Histological, Chemical, and Crystallographic Analysis of Four Calcium Phosphate Cements in Different Rabbit Osseous Sites, J Biomed Mater. Res. [Appl. Biomater.] 43:451-461, 1998; Miyamoto et al., Histological and Compositional Evaluations of Three Types of Calcium Phosphate Cements When Implanted in Subcutaneous Tissue Immediately After Mixing, J. Biomed. Mater. Res. [Appl. Biomater.] 48:36-42, 1999; Lee et al., Alpha-BSM(R): A Biomimetic Bone Substitute and Drug Delivery Vehicle, Clin. Orthop Rel. Res. 367:396-405, 1999. Because of its chemical and crystallographic similarity to the carbonated apatitic calcium phosphate mineral found in human bones and teeth, hydroxyapatite has been one of the most often used restorative materials for the repair of human hard tissues. One of the calcium phosphate compositions, developed by Brown and Chow in 1986 and named calcium phosphate cement, or CPC, self-hardens to form hydroxyapatite as the primary product. The term “self-harden” refers to the paste being able to harden by itself. For example, the CPC paste can be placed into a bone cavity and self-harden subsequent to contact with an aqueous medium. CPC typically may be comprised of particles of tetracalcium phosphate (TTCP: Ca4(PO4)2O) and dicalcium phosphate anhydrous (DCPA: CaHPO4) that react in an aqueous environment to form solid hydroxyapatite, Ishikawa et al., Reaction of Calcium Phosphate Cements with Different Amounts of Tetracalcium Phosphate and Dicalcium Phosphate Anhydrous, J. Biomed. Mater: Res. 46:504-510, 1999; Matsuya et al., Effects of Mixing Ratio and Ph on The Reaction Between Ca4[PO4]2O and CaHPO4, J. Mater. Sci.:Mater. in Med 11:305-311, 2000; Takagi et al., Morphological and Phase Characterizations of Retrieved Calcium Phosphate Cement Implants, J. Biomed. Mater. Res. [Appl. Biomater.]58:36-41, 2001.
Calcium phosphate compositions (such as CPC) are highly promising for a wide range of clinical uses due to their excellent biocompatibility, osteoconductivity and bone replacement capability. For example, CPC has been studied for use in the reconstruction of frontal sinus and augmentation of craniofacial skeletal defects (Shindo et al., Facial Skeletal Augmentation Using Hydroxyapatite Cement, Arch. Otolaryngol. Head Neck. Surg., 119:185-190, 1993), endodontics (Sugawara et al., In vitro Evaluation of the Sealing Ability of a Calcium Phosphate Cement When Used as a Root Canal Sealer-Filler, J. Endodont. 16:162-165, 1990), and root canal applications (Chohayeb et al., Evaluation of Calcium Phosphate as a Root Canal Sealer-Filler Material, J. Endodont. 13:384-387,1987). However, these examples of self-hardening calcium phosphate materials are mechanically weak. That is, the low strength and susceptibility to brittle catastrophic fracture of CPC have severely limited its use to only non load-bearing applications. The use of CPC “is limited to the reconstruction of non-stress-bearing bone” (Costantino et al., Experimental Hydroxyapatite Cement Cranioplasty, Plast. Reconstr. Surg. 90:174-191, 1992), and “clinical usage was limited by . . . brittleness . . . ” (Friedman et al., BoneSource™ Hydroxyapatite Cement: a Novel Biomaterial for Craniofacial Skeletal Tissue Engineering and Reconstruction, J. Biomed. Mater. Res. [Appl. Biomater] 43:428-432, 1998).
The already weak biomaterials are made even weaker when macropores are built into them. In this regard, macropores have been built into biomaterials to facilitate bony ingrowth and implant fixation (LeGeros, Biodegradation and Bioresorption of Calcium Phosphate Ceramics, Clin. Mater. 14:65-88, 1993; Simske et al., Porous Materials For Bone Engineering, Mater. Sci. Forum 250:151-182, 1997; Suchanek et al., Processing and Properties of Hydroxyapatite-Based Biomaterials for use as Hard Tissue Replacement Implants, J. Mater. Sci. 13:94-117, 1998). One advantage of CPC is that it can form macroporous hydroxyapatite implants in situ without involving sintering and machining. But it has been found that macropores degrade the initial implant strength. Studies showed that the strength of CPC, which was already low without macropores, degraded precipitously by an order of magnitude with macropores (Xu et al., Strong and Macroporous Calcium Phosphate Cement: Effects of Porosity and Fiber Reinforcement on Mechanical Properties, J. Biomed. Mater. Res., 57:457-466, 2001). On the other hand, after macroporous materials are implanted, the strength of the implants significantly increases once new bone starts to grow into the macropores (Shors et al., Porous Hydroxyapatite, pp. 181-198 in Hency et al., An Introduction to Bioceramics, World Sci. Pub., NJ, 1993). Therefore, it is in the early stage of implantation when a macroporous CPC type implant is in the most need of strength and toughness.
In other words, the major challenge for brittle materials like calcium phosphate cements is to withstand tensile stresses which can cause catastrophic fracture. This results since most load-bearing situations usually involves tensile stress components. The ability of such material to resist tensile stresses can be characterized in tests of uniaxial tension, bending, flexure, or diametral tension, which are more demanding than compression tests. U.S. Pat. Nos. 5,525,148, 5,545,254, 5,976,234, and 5,997,624 (Chow et al.) disclose cements that achieved strength values in diametral tension for calcium phosphate cements ranging from less than 1 Mpa to less than 10 Mpa (1 Mpa=106 Neutrons per square meter). This is considered to be too low for useful application of bone replacement in high stress regions in vivo.
Xu et al. suggested fiber reinforcement of calcium phosphate cement in “Reinforcement of a Self-Setting Calcium Phosphate Cement with Different Fibers”, J. Biomed. Mater. Res. 52:107-114 (2000) and in “Effects of Fiber Length and Volume Fraction on the Reinforcement of Calcium Phosphate Cement”, J. Mater. Sci.: Mater. In Med. 12:57-65 (2001). Von Gonten et al. suggested a single sheet of mesh reinforcement for calcium phosphate cement in “Load-Bearing Behavior of a Simulated Craniofacial Structure Fabricated from a Hydroxyapatite Cement and Bioresorbable Fiber-Mesh”, J. Mater. Sci.: Mater. In Med. 11:95-100 (2000). However, there has been no mention of producing macropores in the calcium phosphate cements, and there has been no mention of controlling the strength history and macropore formation rates.
Takagi et al. suggested the formation of macropores resulting from the dissolution of soluble fillers or pore forming agents in “Formation of Macropores in Calcium Phosphate Cement Implants”, J. Mater. Sci.: Mater. In Med. 12:135-139 (2001). However, the strength in diametral tension decreased to as low as 0.4 Mpa, and there was no mention of controlling the strength history and the rates of macropore formation. Chow reviewed calcium phosphate cements in “Calcium Phosphate Cements: Chemistry, Properties, and Applications”, Mat. Res. Symp. Proc. 599:27-37 (2000). He mentioned the use of bioresorbable reinforcement fibers and the incorporation of pore forming agents, and acknowledged that “Incorporating macropores into the cement has always led to a significant decrease in mechanical strength”, lines 22-23, page 24. There was no mention in his paper of methods that actually increase the strength while producing macropores. There was no mention of fabricating implants with multiple layers with designed functions for each layer for strength or macropores. Xu et al. incorporated fibers and pore forming agents in “Strong and Macroporous Calcium Phosphate Cement: Effects of Porosity and Fiber Reinforcement on Mechanical Properties”, J. Biomed. Mater. Res. 57:457-466, (2001). Only a single type of fiber was used, which did not lead to, and the authors did not mention, the control of strength history. In addition, only a single type of pore forming agent was used, which did not lead to, and the authors did not mention, the tailoring of the macropore formation rate. Xu et al. used resorbable fibers in “Calcium Phosphate Cement Containing Resorbable Fibers For Short-term Reinforcement and Macroporosity”, Biomaterials 23:193-202 (2002). Only a single type of fiber was used in each specimen and there was no mention of ways to control the specimen's strength history and macropore formation rates. Furthermore, there was no mention of fabricating implants with multiple layers with specific functions for each layer for strength and macropores in these self-hardening calcium phosphate materials.
U.S. Pat. No. 5,652,056 (Pepin) discloses hydroxyapatite filaments reinforcement. U.S. Pat. No. 6,077,989 (Kandel et al.) discloses condensed calcium phosphate particles. U.S. Pat. No. 6,136,029 (Johnson et al.) discloses bone substitute material comprising of a sintered, load-bearing framework. U.S. Pat. No. 6,287,341 (Lee et al.) discloses ceramic implants comprising an amorphous or poorly crystalline calcium phosphate. None of this prior art mentions methods of combining absorbables fibers or meshes and other stable or degradable fillers of different dissolution rates, or methods of implants with multiple layers having specific functions for each layer, that result in the control of strength histories and the tailoring of macropore formation rates.
U.S. Pat. No. 4,512,038 (Alexander et al.) discloses a composite of a bio-absorbable polymer and carbon fibers. U.S. Pat. No. 4,655,777 (Dunn et al.) discloses a composite of resorbable fibers in a biodegradable polymer matrix. U.S. Pat. No. 4,963,151 (Dueheyne et al.) discloses methods of short and fine fibers distributed homogeneously throughout surgical bone cement. U.S. Pat. No. 5,181,930 (Dumbleton et al.) discloses continuous carbon fibers and a polymer matrix. U.S. Pat. No. 5,192,330 (Chang et al.) discloses oriented fiber reinforcement in a polymer. U.S. Pat. No. 5,556,687 (McMillin) discloses orientations of reinforcing fibers in preforms that are heated and consolidated in a mold. U.S. Pat. No. 5,721,049 (Marcolongo et al.) discloses composites of bioactive glass and ceramic fibers. U.S. Pat. No. 5,766,618 (Laurencin et al.) discloses methods of three-dimensional macroporous polymer matrices that contain hydroxyapatite particulates. U.S. Pat. No. 6,214,008 (Illi) discloses biodegradable implants made of a polymeric biodegradable base material. U.S. Pat. No. 6,281,257 (Ma et al.) discloses three-dimensional porous matrices as structural templates for cells. None of this prior art is related to self-hardening calcium phosphate materials. Furthermore, none mentions methods of combining absorbables fibers or meshes and other fillers of different dissolution rates that result in the control of strength histories and the tailoring of macropore formation rates. In addition, none mentions methods of implants with multiple layers having gradient properties and specific functions for each layer, for example, for strength and/or macropore formation.
U.S. Pat. No. 6,207,098 (Nakanishi et al.) discloses methods of water-soluble polymer or other pore forming agent for producing porous materials. U.S. Pat. No. 6,281,256 (Harris et al.) discloses preparation of porous polymers by a combination of gas forming and particulate leaching steps. None of this prior art reveals methods of strengthening and toughening the materials while producing pores. Furthermore, none mentions methods of combining absorbables fibers or meshes and other fillers of different dissolution rates, or methods of implants with multiple layers having specific functions for each layer, that result in the control of strength histories and the tailoring of macropore formation rates.
In conclusion: (1) There has been no mention in the known prior art of methods of fabricating self-hardening calcium phosphate materials that contain multiple layers with specific functions for each layer for strength and macropore formation, or methods of incorporating, multiple types of fillers and fiber materials with varied dissolution rates for controlled strength histories and tailored macropore formation rates. (2) There has been no mention of methods of effectively and substantially increasing material strength and toughness while producing macropores for vascular and bone ingrowth. (3) There has been no mention in the known prior art of controlling the material strength history and macropore formation rates by mixing absorbable fibers or meshes of fast dissolution rates together with absorbable fibers or meshes of slow dissolution rates. In this way, when the fibers and meshes with faster dissolution rates dissolve and create macropores for bony ingrowth, the fibers and meshes with slow dissolution rates provide longer-term reinforcement. After significant bone ingrowth into the macropores to increase the strength of the implant, the fibers and meshes with slow dissolution rates will then dissolve to create additional macropores for further ingrowth. (4) There has been no mention in the known prior art of self-hardening calcium phosphate materials and implants that contain two or more layers, wherein bone can first grow into a macroporous external layer of the implant, with absorbable fibers or meshes in the second layer providing initial strength but then dissolve to create macropores for further ingrowth, while a strong inner layer with fibers having a slow dissolution rate still maintains reinforcement. Eventually, with significant bone ingrowth into the macropores increasing the implant strength, the slowly-absorbable fibers in the inner layer of the implant dissolve and form macropores for continued bone ingrowth.